PROJECT SUMMARY-ABSTRACT The purpose of the proposed study is conduct a controlled investigation of HIV host and viral dynamics on brain integrity in vertically infected children on stable combined antiretroviral therapy (cART) in Myanmar. Outcomes from the PREDICT trial in Southeast Asia revealed residual cognitive impairment among pediatric HIV+ individuals with vertical infection. Socioeconomic variables predicted cognitive test performance among infected children and children exposed to HIV but uninfected with the virus. Efforts to define the neuropathogenesis of HIV require adequate control of these environmental variables known to influence cognitive test performance and engagement in ADLs. The majority of HIV+ children in Myanmar reside in privately funded orphanages with standardized caregiver status, nutrition, and education. Our preliminary work reveals cognitive impairment in these children on cART with high CD4 count when compared to demographically matched healthy controls (HIV-). Further, 40% of the HIV+ children express preferential use of the CXCR4 co-receptor and the degree of cognitive impairment is greater among these children compared to those expressing the CCR5 co-receptor despite similar CD4 counts. Previous studies have associated CXCR4 utilization with worse cognition in HIV+ adults with advanced disease, but it is unclear from these studies if co-receptor subtype is liked to cognitive impairment or more simply a correlated variable between disease severity and cognitive impairment. Our preliminary data suggests a mechanistic role for CXCR4 on reduced brain integrity independent of advanced disease, emphasizing the need to identify the relevant immunological factors. Work from our team previously demonstrated that circulating monocyte HIV content, monocyte subpopulations, and myeloid-derived immunological mediators are key mechanisms of HIV-associated neurocognitive impairment. The present study will examine these immunological mechanisms and co-receptor tropism in the cascade of events related to cognitive impairment in vertically infected youth. This information is critical to facilitate the development of targeted treatments to improve cognitive function among children with vertically infected HIV. We will enroll 120 HIV+ vertically infected children and adolescents between the ages of 8 and 15 and 60 HIV- controls matched for demographics, and all residing in privately funded orphanages. Neuropsychological, virological, and immunological assays will be completed to determine pediatric HIV neuropathogenesis in the context of stable cART.